Identifying cellular and molecular signatures from distinct T cell receptor clonotypes associated with favorable immune checkpoint inhibitor responses in HNSCCs

识别与 HNSCC 中有利的免疫检查点抑制剂反应相关的不同 T 细胞受体克隆型的细胞和分子特征

• 批准号: 10573334
• 负责人: Robert L. Ferris
• 金额: $ 68.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573334
• 关键词: Adjuvant Study; Aftercare; Antibodies; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cancer Prognosis; Carcinogens; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinical; Clinical Trials; Clonal Expansion; Combination immunotherapy; Coupled; Data; Disease; Future; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Immune checkpoint inhibitor; Institution; Link; Modeling; Molecular Profiling; Mus; Neoadjuvant Therapy; Nivolumab; Pathway interactions; Patients; Peripheral; Peripheral Blood Lymphocyte; Phenotype; Population; Publishing; Resectable; Sampling; Splenocyte; Surrogate Markers; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Tumor Antigens; Tumor Expansion; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Validation; anti-CTLA4; anti-PD-1; anti-PD-L1; anti-PD-L1 therapy; antigen-specific T cells; cancer immunotherapy; cancer type; checkpoint therapy; improved; insight; minimally invasive; molecular marker; mouse model; novel; programmed cell death protein 1; response; single-cell RNA sequencing; transcriptome; transcriptomics; tumor

Project Summary/Abstract Cancer immunotherapy has become one of the pillar therapies in treating cancer patients, exemplified by immune checkpoint inhibitors (ICI) (e.g., anti-PD1). While ICIs have significantly improved the prognosis of cancer patients, the response rate to ICI monotherapy remains low (10-20%) for many types of cancer, such as head and neck squamous cell carcinoma (HNSCC). Some variability may be explained by human papillomavirus (HPV)- vs. carcinogen-induced, tumor antigen-specific T cell responses in HPV+ or HPV− HNSCC, reflecting a unique disease opportunity to investigate ICI responsiveness. Thus, it is vital to better understand the mechanisms underlying heterogenous responses to ICI and to identify new targets that may sensitize HNSCCs to mono- and combination immunotherapy. In this application, we propose to focus on T cell phenotypes associated with clinical response, dynamic changes in specific T cell receptor (TCR) clonotypes, and TCR clonotype-specific transcriptomic changes in response to ICI treatment, using HNSCC patient samples from an ongoing clinical trial at our institution and detailed studies using murine HNSCC models. Using HCC 18-139 trial samples, we will compare tumor infiltrating lymphocytes (TIL) and peripheral blood lymphocytes (PBL) from pre- and post-treatment samples and examine TCR dynamics and T cell phenotypes in blood (minimally invasive and readily accessible) and in tumors in the context of ICI-induced anti-tumor immunity. Our mouse model allows functional validation among distinct TCR clonotypes correlating with ICI responses, and permits manipulation of novel potential targets to enhance clinical responsiveness as well as lay the groundwork for future clinical trials. Our proposed studies will identify cellular and molecular markers to better predict ICI responses in HNSCC patients treated with different combinations of ICIs and would facilitate finding novel mechanisms of differential ICI responses using transcriptomic differences in distinct clonal TCR-bearing T cell populations. A unique strength of our proposal is integration of human clinical trial samples and mouse models as a more powerful platform to uncover mechanistic insights that are translatable into the clinical setting.

项目摘要/摘要 癌症免疫疗法已成为治疗癌症患者的支柱疗法之一，例如 免疫检查点抑制物(ICI)(例如，抗PD1)。而ICIS显著改善了患者的预后 对于癌症患者，对于许多类型的癌症，ICI单一疗法的应答率仍然很低(10%-20%)，例如 头颈部鳞癌(HNSCC)。一些变异可以用人类乳头瘤病毒来解释 在HPV+或HPV−人非小细胞癌中，HPV-与致癌物诱导的肿瘤抗原特异性T细胞反应，反映了 调查ICI响应性的独特疾病机会。因此，更好地理解 ICI异质性反应的潜在机制和识别可能使HNSCCs增敏的新靶点 单一免疫疗法和联合免疫疗法。在本应用中，我们建议重点研究T细胞表型 与临床反应、特异性T细胞受体(TCR)克隆型和TCR的动态变化相关 使用HNSCC患者样本对ICI治疗的反应的克隆型特异性转录变化 我们机构正在进行临床试验，并使用小鼠HNSCC模型进行详细研究。使用肝细胞癌18-139试验 样本，我们将比较肿瘤浸润性淋巴细胞(TIL)和外周血淋巴细胞(PBL) 并检测血液中TCR动态和T细胞表型(微创和 容易获取)和在ICI诱导的抗肿瘤免疫的背景下的肿瘤中。我们的鼠标模型允许 与ICI反应相关的不同TCR克隆类型之间的功能验证，并允许操纵 新的潜在目标，以提高临床响应性以及为未来的临床试验奠定基础。 我们建议的研究将确定细胞和分子标志物，以更好地预测HNSCC的ICI反应 患者接受不同的ICIS组合治疗，将有助于发现新的分化机制 ICI反应利用不同克隆性携带TCR的T细胞群体的转录差异。独一无二的 我们建议的优点是将人类临床试验样本和小鼠模型整合为更强大的 揭示可转化为临床环境的机械性见解的平台。